Cancer cells appear to undergo autophagy in response to oral hypoglycemic agents. Autophagy, or type II programmed cell death, is a catabolic process whereby cells self-digest intracellular organelles. Autophagy is an evolutionarily conserved, genetically controlled process that results in the targeting of cellular proteins and organelles to lysosomes for degradation. Autophagy is a dynamic process and the role of autophagy in cancer is complex and may differ depending on tumor type or context. Autophagy may serve to regulate normal turnover of organelles and to remove those with compromised function to maintain homeostasis. However, autophagy can also be considered a temporary survival mechanism during periods of starvation where self-digestion provides an alternative energy source and also may facilitate the disposal of unfolded proteins under stress conditions. Many agents used to prevent and to treat malaria are inhibitors of autophagy.
One characteristic of cancer cells is they often do not undergo apoptosis. Chemotherapy is used to eliminate these non-apoptotic cells. However, recurrence of cancer subsequent to chemotherapy is observed in some patients. GTPase KRas, also known as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog and KRAS, is a protein encoded by the KRAS gene in humans. Like other members of the Ras family, the KRAS protein is a GTPase and is an early player in many signal transduction pathways. KRAS is usually tethered to cell membranes because of its C-terminus isoprenyl group. The protein product of the normal KRAS gene performs an essential function in normal tissue signaling, and the mutation of a KRAS gene is an essential step in the development of many cancers. In particular, cancer cells harboring specific KRAS mutations, for example a glycine to valine substitution at codon 12 (G12V) in K-Ras gene, have been associated with reduced overall survival in many cancers. The transforming protein that results is implicated in various malignancies; nonlimiting examples include lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma.
Using colorectal cancer as an example, mutations in KRAS are involved in 22-46% of colorectal carcinogenesis. Mutations in the K-Ras gene, especially a glycine to valine substitution at codon 12 (G12V), have been proposed to be an independent risk factor for reduced overall survival in colorectal cancer patients. The presence of mutations in the K-Ras gene has been associated with the lack of response to anti-EGFR monoclonal antibody treatment. Thus, there is increasing clinical relevance in the detection of mutations in the K-Ras gene with sensitive molecular methods to improve risk stratification and therapeutic strategies.
Patients with Type II diabetes taking oral drugs used to lower blood sugar have a significantly lower incidence of cancer. However, these drugs, i.e., oral hypoglycemic drugs such as buformin, metformin, phenformin and pioglitazone, when used in the treatment of patients with later stage cancers have not shown significant anticancer activity. Therefore, there remains a need to improve and develop new cancer treatments, and to reduce the incidence of recurrence. There remains a need to identify new cancer treatment methods, and new compositions and compounds useful to treat cancer.